Effect of discontinuous acyclovir treatment on in vitro reactivation of herpes simplex virus from latently infected trigeminal ganglia.

Exposing explant cultures of latently infected mouse trigeminal ganglia alternately to acyclovir-containing and drug-free medium led to a significant decrease in the proportion of ganglia containing reactivatable herpes simplex virus. The loss of virus from the explant cultures was not caused by thermal inactivation during prolonged incubation periods. The efficiency of virus elimination may depend on the frequency and duration of the alternating treatment and on the number of latently infected neurons in the ganglia.

Dissemination of herpes simplex virus in ganglia after footpad inoculation in neurectomized and non-neurectomized mice.

After unilateral footpad inoculation with herpes simplex virus (HSV) the infection spreads initially to the ipsilateral and afterwards to the contralateral spinal ganglia. In about 25 percent of the mice the virus also reaches the trigeminal ganglia. Furthermore, we have shown that only a complete severance of the nervous connections can prevent the colonization of ganglia with HSV after footpad inoculation. Results of previous experiments in which only the sectioning of the sciatic nerve was able to prevent the invasion of ganglia, are difficult to explain. It appears also that HSV travels in the nerve toward the ganglia in a non-infectious form, and that the infectious virus detectable in nerves originates not from the peripheral inoculation site, but from the infectious virus pool which accumulates in spinal ganglia. A limited role of the circulatory system in the colonization of sensory ganglia by HSV cannot be excluded, since in a few cases virus was detected in ganglia after sectioning of both the sciatic and the femoral nerve.

Acid-labile human leukocyte interferon in homosexual men with Kaposi's sarcoma and lymphadenopathy.

Some immunologic parameters in homosexual patients with Kaposi's sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-alpha) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of HuIFN had antiviral activity on bovine cells, a characteristic of HuIFN-alpha, and all of 14 representative samples tested were neutralized by antibody to HuIFN-alpha. In addition, the HuIFN-alpha in six of eight representative patients was inactivated at pH 2 and therefore appears to be similar to the HuIFN-alpha found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.

Pathogenesis of experimental skin infections induced by drug-resistant herpes simplex virus mutants.

The comparative analysis of the pathogenicity of a parental herpes simplex virus type 1 strain and its phosphonoacetic acid (PAA)-resistant and acyclovir (ACV)-resistant mutants showed marked differences among them. After orofacial skin inoculation of hairless mice the parental and PAA-resistant viruses were detected during the first 4 days after infection at high and increasing titers in the trigeminal ganglia; the ACV-resistant mutant was present at low and decreasing titers in the ganglia. Severe and slow-healing skin lesions were produced by the parental and PAA-resistant viruses; mild and rapidly healing lesions were produced by the ACV-resistant mutant. Virus titers in ganglia and the intensity of skin lesions were related to the virus dose used in the primary infection. Latent infections became established in trigeminal ganglia of mice inoculated with 10(6.0) plaque-forming units of the parental or PAA-resistant virus; no latent infections were detected in ganglia of mice inoculated with 10(7.0) plaque-forming units of the ACV-resistant mutant. Serum antibody titers attained similar values 4 weeks after primary infection with both mutants and the parental virus. Mice infected with the ACV-resistant mutant were reinfected with the parental and PAA-resistant viruses; the degree of protection against development of skin lesions, mortality, and latency was related to the dose of ACV-resistant virus used in the primary infection. Mortality was prevented by a dose of 10(6.0) plaque-forming units, skin lesions were prevented by a dose of 10(6.5) plaque-forming units, and latency was prevented by a dose of 10(7.0) plaque-forming units of the ACV-resistant mutant. Protection against reinfection with the PAA-resistant mutant was achieved with lower doses than protection against the parental virus. Serum antibody titers showed a 4- to 15-fold increase after reinfection. The results suggest that the ACV-resistant, latency-negative mutant has many attributes of a live attenuated herpes simplex virus vaccine.

Effect of acyclovir on latent herpes simplex virus infections in trigeminal ganglia of mice.

The inhibition by acyclovir of the in vitro reactivation of herpes simplex virus from latently infected ganglion explant cultures is dependent on the continuous presence of this drug. Administration of acyclovir subcutaneously, orally, or by continuous perfusion to mice with established latent infections did not eliminate latent virus from the trigeminal ganglia.

Experimental skin infection with an acyclovir resistant herpes simplex virus mutant: response to antiviral treatment and protection against reinfection.

Skin infections induced in hairless mice with an Acyclovir resistant herpes simplex virus (HSV) mutant were not followed by the death of the animals, and the survivors had no evidence of latent infections in their sensory ganglia. However, mutant virus was detected in the ganglia during the acute phase of the infection. Mice inoculated with the mutant were fully protected against the fatal outcome of the infection when subsequently challenged with the relatively pathogenic parental virus. In addition the frequency of latent infections established after challenge was significantly reduced. Phosphonoacetic acid treatment of the primary mutant-induced infection abolished the protection against reinfection with parental virus. Acyclovir treatment of the primary infection with the mutant virus did not affect the protection against reinfection with parental virus. The results indicate that drug-resistant, latency-negative, HSV mutants are a promising starting point for the development of an attenuated HSV vaccine.

Latent infections of sensory ganglia as influenced by phosphonoformate treatment of herpes simplex virus-induced skin infections in hairless mice.

Topical treatment with 3% phosphonoformate of herpes simplex virus type 1 (HSV)-induced skin infections of hairless mice reduced the severity of skin lesions when the treatment was initiated 3 h after virus inoculation in the lumbosacral area or 3 and 24 h after inoculation in the orofacial area. The mortality was significantly reduced in lumbosacral-infected mice and was completely prevented in orofacial-infected mice when the treatment was initiated with a delay of 24 h after virus inoculation. However, phosphonoformate did not prevent the establishment of latent herpes simplex virus type 1 infections in the spinal and trigeminal ganglia, even when treatment was initiated as early as 3 h after infection.

Latent herpes simplex virus infections in sensory ganglia of hairless mice prevented by acycloguanosine.

Acycloguanosine (ACG) was able to prevent the fatal outcome of herpes simplex virus-induced skin infections of the lumbosacral or orofacila area in hairless mice. Topical ACG treatment was more effective than systemic treatment in preventing the evolution of skin lesions. Acute ganglionic infections in the trigeminal ganglia were prevented by ACG, and latent ganglionic infections did not become established when the ACG treatment was initiated 3 h after infection. Serum antibody titers were, on the average, eight times higher in mice which developed latent ganglionic infections after ACG treatment than in mice without evidence of herpes simplex virus latency in ganglia. Reinoculation of ACG-treated mice at a site different from that of the primary inoculation did not lead to the establishment of a second latent infection with the homologous virus type when a latent infection was already present. In mice without evidence of latent infection after the primary inoculation, a latent infection at the site of reinoculation became established in 25% of the animals.